Medical Device with Crystalline Drug Coating

ABSTRACT

A medical device having a polymer-free outer surface layer comprising a crystalline drug selected from the group consisting of everolimus, tacrolimus, sirolimus, zotarolimus, biolimus, and rapamycin. The device may be produced by a method comprising the steps of providing a medical device; applying a solution of the drug to said portion of the outer surface to form a coating of amorphous drug; and vapor annealing the drug with a solvent vapor to form crystalline drug; wherein a seed layer of a crystalline form of said drug having a maximum particle size of about 10 μm or less is applied to at least said portion of the outer surface of the device before or after applying the drug solution, but before vapor annealing the amorphous coating.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 13/242,445,filed on Sep. 23, 2011, which claims the benefit of U.S. ProvisionalApplication No. 61/527,203, entitled, “Medical Device with CrystallineDrug Coating,” by Steve Kangas, James Feng, Maggie Zeng, and Yen-LaneChen, and filed on Aug. 25, 2011, the entire contents of which beingincorporated herein by reference.

BACKGROUND OF THE INVENTION

Medical devices such as catheters, stents or balloons coated with drugssuch as paclitaxel and sirolimus, tacrolimus or everolimus, are known.Frequently the drug is compounded with, or absorbed into, a polymer, oris absorbed into a porous material or is coated under a polymer. Thesetechniques can provide for extended release of the drug, but theyintroduce complicating structural and biocompatibility issues.

Attempts to provide drug coatings that do not include polymers and thatprovide for extended release of the drug have presented skilled medicaldevice designers with special difficulty.

The problem of providing a polymer-free drug coating specifically onstents is complicated in that a drug coating on the stent should surviveexpansion of the stent and remain in place until absorbed into tissue ordissolved into the bloodstream. Similar problems exist with otherimplanted medical devices that are left in the body for extended periodssuch as artificial heart valves, indwelling catheters, vascular grafts,vena cava filters, stent grafts and the like.

It is desirable however to have an drug coating comprising crystallinedrug and at the same time utilizes no polymer. This is a problem becausetechniques for depositing drug directly on a substrate in crystallineform without a polymer produce very poor adhesion, and other techniquesfor depositing amorphous drug and then converting it to crystallineform, for instance as described in US 2010/0272773 and US 2011/0015664,commonly owned, and the latter proposes to nucleate the surface,however, the nucleating agent is taught as desirably one that is notsoluble in the solvent used to apply the drug, which precludes using thedrug itself as a nucleating agent. Water soluble substances areindicated to be preferable.

SUMMARY OF THE INVENTION

The invention in some aspects pertains to a medical device having apolymer-free outer surface layer on at least a portion thereof, saidlayer comprising a crystalline drug selected from the group consistingof everolimus, tacrolimus, sirolimus, zotarolimus, biolimus, andrapamycin.

In other aspects the invention pertains to a method of forming a coatingcomprising a drug onto at least a portion of an outer surface of amedical device comprising the steps of

providing a medical device;

applying a solution of the drug to said portion of the outer surface toform a coating of amorphous drug; and

vapor annealing the drug with a solvent vapor to form crystalline drug;

wherein a seed layer of a crystalline form of said drug having a maximumparticle size of about 10 μm or less is applied to at least said portionof the outer surface of the device before or after applying the drugsolution, but before vapor annealing the amorphous coating. The drug maybe everolimus, tacrolimus, sirolimus, zotarolimus, biolimus, andrapamycin, or other macrolide immunosuppressive drug.

Particularly preferred aspects pertain to such devices and methods wherethe drug is everolimus and/or where the device is a stent.

Further aspects pertain to such devices or coatings where the drugcoating is provided on the stent or the vapor annealing process iscontrolled to produce a predetermined mixture of crystalline andamorphous drug on the device. Still further aspects of the inventionpertain to such medical devices wherein the crystalline form of the drugis formed by individual crystals having with an average length of lessthan 50 μm, an average width of less than 10 μm and an average thicknessof less than 1.5 μm.

These and other aspects and embodiments of the invention are describedin the Detailed Description, Claims and Figures which follow.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph comparing everolimus solubility data in water @ 37° C.for amorphous and crystalline forms.

FIG. 2 is an enlarged SEM of the crystalline structure of a stentcoating of the invention.

FIG. 3 shows a representative SEM of the seeded stent showing traces ofmicrocrystalline everolimus.

FIG. 4 shows a representative SEM of a stent coated with amorphouseverolimus using a nominal spray process which provides a smoothcoating.

FIGS. 5 a and 5 b show a representative SEM of a stent coated withamorphous everolimus using a dry spray process, at two differentmagnifications.

FIG. 6 shows a representative SEM of a vapor annealed seeded stent(using the nominal everolimus coating).

FIGS. 7 a and 7 b show representative SEM of a vapor annealed seed stent(using the dry everolimus coating process), at two differentmagnifications. A very small, uniform crystalline structure is formedduring vapor annealing.

FIGS. 8 a and 8 b show a stent coated with amorphous everolimus (FIG. 8a), and after vapor annealing without seeding (FIG. 8 b) for comparativepurposes.

FIG. 9 shows SEM images of a coated balloon as described in Example 4,at 4 magnifications.

FIG. 10 shows SEM images of a coated balloon as described in Example 3.

FIG. 11 shows an example of a coating discrete dots of a drug on asubstrate.

FIG. 12 depicts a portion of a stent having dots of crystalline drugthereon.

FIG. 13 depicts a portion of a stent having dots of crystalline drug anddots of amorphous drug thereon.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Earlier investigations of paclitaxel coated balloons by the applicanthave shown that it is desirable to control the morphology of the drug onthe balloon, that crystalline form drugs can facilitate longer tissueresidence time, and that the formation of crystalline paclitaxeldihydrate can be controlled by use of vapor annealing of the balloon.Copending US applications, Ser. No. 12/765,522 filed Apr. 24, 2010,published as US 2010/0272773 A1, claiming priority of provisionalapplication 61/172,629; and Ser. No. 12/815,138, filed Jun. 14, 2010,published as US 2011/0015664 A1 and claiming priority of provisionalapplication 61/271,167; all incorporated herein by reference in theirentirety, describe this work in more detail.

In copending U.S. provisional application 61/515,500, also incorporatedherein by reference in its entirety, techniques for forming crystallineeverolimus or another macrolide drug from slurries of amorphous drughave been described. The crystalline form has a lower water solubilityand that lower solubility has several advantages, including permitting alower drug coat weight needed to provide an therapeutic dose at thedevice location over an extended period and allowing for manipulation ofthe release rate independent of a polymer. Achieving these advantages inpractice, however, depends on an ability to provide a reliably adherentcoat of drug without any polymer present. The present invention pertainsto devices and methods in which a crystalline form drug coating isformed on a device from an amorphous drug coating layer by seeding asurface of the device, before or after application of the amorphous druglayer, and then vapor annealing the coating with a solvent vapor.

Everolimus is supplied by the vendor as an amorphous solid. Coating adevice with an everolimus coating solution leads to a coating in whichthe everolimus is in the amorphous state. Given the fact that theaqueous solubility of amorphous everolimus is greater than amorphouspaclitaxel, and amorphous paclitaxel dissolves too rapidly to providesustained drug tissue levels when delivered without a polymer tomodulate release, it is likely that it will not be possible to attainadequate drug tissue duration with a drug eluting balloon (DEB) based onamorphous everolimus without use of a polymer. Formulations withpolymers, however, are undesirable because placing a polymer at thetreatment site introduces a complicated set of tissue compatibility anddegradation issues which may be different for each drug or drug formused and for delivery at different tissue sites.

Studies by the owner of this application have shown that crystallineeverolimus has a much lower solubility in water than amorphouseverolimus. Everolimus solubility data (in water @ 37° C.) is shown inFIG. 1. A medical device such as a stent or balloon having apolymer-free coating based on a crystalline drug such as everolimus isuseful for obtaining a dissolution-controlled drug release coating thatdoes not rely on polymer.

FIG. 2 is an SEM of an everolimus drug coating on a stent prepared inaccordance with the invention. The figure shows tightly packedrectilinear crystals having an estimated length of about 5-15 μm, widthof about 0.5-1.5 μm and thickness of about 0.3 μm, based on the scaleprovided at the lower left of the figure.

Drugs

According to some embodiments of the invention the drug is one that hascrystalline and amorphous forms, and is desirably delivered in a crystalform. The drugs which can be used in embodiments of the presentinvention, can be any therapeutic agent or substance that hastherapeutic benefit for local administration by delivery from a medicaldevice inserted into the body and that also exists in such polymorphforms. In this aspect the drug is coated on the device, with or withoutan excipient, in an amorphous form and then is converted to the desiredcrystalline form in an annealing step that grows the crystalline drug inthe coating in-situ on the device. This gives a packed system ofcrystals on the surface that more closely approximate the desiredproperties of a drug delivery balloon.

In some embodiments the drug is a lipophilic substantially waterinsoluble drug that inhibits restenosis, for instance rapamycin,rapamycin analogous and derivatives, everolimus, everolimus analogousand derivatives, paclitaxel analogous and derivatives, and mixturesthereof. The drug is suitably one that is able to form a crystallineform by treatment with a solvent or solvent vapor after it is applied tothe device.

In some embodiments, the drug may be a macrolide immunosuppressive(limus) drug. In some embodiments, the macrolide immunosuppressive drugis rapamycin, biolimus (biolimus A9), 40-O-(2-Hydroxyethyl)rapamycin(everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-0-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus),42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus), (42S)-42-Deoxy-42-(1H-tetrazol-1-yl)-rapamycin(zotarolimus), or derivative, isomer, racemate, diastereoisomer,prodrug, hydrate, ester, or analog thereof, provided that the particulardrug is one has an amorphous form and a crystalline form.

In some embodiments, the drug may be everolimus, sirolimus, zotarolimusand/or biolimus. In some embodiments the drug is everolimus.

Other drugs for which the inventive conversion method that may be usefulinclude include antiinflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine,mesalamine, and analogues thereof;antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, thymidine kinase inhibitors, and analoguesthereof; anesthetic agents such as lidocaine, bupivacaine, ropivacaine,and analogues thereof; anti-coagulants; and growth factors, againprovided that the particular drug is one has an amorphous form and acrystalline form.

Excipients

In some embodiments the drug is formulated with a non-polymericexcipient. An excipient is an non-polymeric additive to adrug-containing layer that facilitates adhesion to the device and/oralters release properties from the device upon placement at a treatmentsite. In at least some embodiments using an excipient the drug issubstantially insoluble in the excipient. In at least some embodimentsusing an excipient, the excipient and amorphous drug are dissolved in acommon solvent which is then applied to the device to form the anamorphous drug layer that further comprises the expedient. An excipientmay also be applied by concurrent spraying of separate solvent solutionsof the drug and the excipient.

Typically the non-polymeric excipient will provide less complicationsbecause it has a much shorter residence time at a treatment site. Thishowever means that it may not have much influence on an extendedresidence time for the drug at the site.

Examples of excipients that may be employed include polymeric andnon-polymeric additive compounds, including sugars such as mannitol,contrast agents such as iopromide, citrate esters such as acetyltributyl citrate, acetyl triethyl citrate, tributyl citrate, triethylcitrate, acetyltri-n-hexyl citrate, n-butyryltri-n-hexyl citrate,acetyltri-n-(hexyl/octyl/decyl) citrate, and acetyltri-n-(octyl/decyl)citrate; glycerol esters of short chain (i.e. C₂-C₈) mono-carboxylicacids such as triacetin; and pharmaceutically acceptable salts.

Exemplary non-polymeric excipients include citrate esters, such asacetyl tributyl citrate or other acetylated trialkyl citrates, trialkylcitrates, and trialkyl citrates that have been etherified at thehydroxyl group on citric acid. Other non-polymeric excipients that maybe useful include surfactants such as described in US 2008/0118544 A1;oils; esters of fatty acids and C₁-C₃₀ alcohols such as isopropylmyristate; triacetin; and the like. Other documents in which describenon-polymeric excipients that may be useful include US 2005/0101522 A1;US 2006/0020243 A1; US 2008/0255509 A1; US 2010/0063585 A1; US2010/0179475 A1; and US 2010/0272773 A1. In at least some embodimentsthe excipient is selected to be one in which the drug is substantiallyundissolved, so that the major portion of the drug remains in thecrystalline form.

In at least some embodiments no excipient is used.

Devices

The medical devices used in conjunction with the present inventioninclude any device amenable to the coating processes described herein.The medical device, or portion of the medical device, to be coated orsurface modified may be made of metal, polymers, ceramics, composites orcombinations thereof. Whereas the present invention is described hereinwith specific reference to a vascular stent or balloon, other medicaldevices within the scope of the present invention include any deviceswhich are used, at least in part, to penetrate the body of a patient.Non-limiting examples of medical devices according to the presentinvention include catheters, guide wires, balloons, filters (e.g., venacava filters), stents, stent grafts, vascular grafts, intraluminalpaving systems, soft tissue and hard tissue implants, such as orthopedicrepair plates and rods, joint implants, tooth and jaw implants, metallicalloy ligatures, vascular access ports, artificial heart housings,artificial heart valves, aneurysm filling coils and other coiled coildevices, trans myocardial revascularization (“TMR”) devices,percutaneous myocardial revascularization (“PMR”) devices, hypodermicneedles, soft tissue clips, holding devices, and other types ofmedically useful needles and closures, and other devices used inconnection with drug-loaded polymer coatings.

Such medical devices may be implanted or otherwise utilized in bodylumina and organs such as the coronary vasculature, esophagus, trachea,colon, biliary tract, urinary tract, prostate, brain, lung, liver,heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas,ovary, cartilage, eye, bone, and the like. Any exposed surface of thesemedical devices which may enter the body may be coated with the coatingand methods of the present invention.

In some embodiments the drug is provided on stents or other devicesimplanted or left in place for extended times in the body. In someembodiments the drugs are deliverable from the surface of catheterballoons which is transiently provided at a site of treatment, expandedto release the drug and then removed. The devices of the presentinvention, may be deployed in vascular passageways, including veins andarteries, for instance coronary arteries, renal arteries, peripheralarteries including illiac arteries, arteries of the neck and cerebralarteries, and may also be advantageously employed in other bodystructures, including but not limited to arteries, veins, biliary ducts,urethras, fallopian tubes, bronchial tubes, the trachea, the esophagusand the prostate.

In some embodiments the invention pertains to a stent coated withpolymer-free coating comprising crystalline everolimus.

Seeding

Some embodiments involve applying an amorphous drug coating to a devicethat has been first nucleated with microparticulate crystalline drug toinduce crystallization during the annealing step. In some embodiments acoating of amorphous drug is applied to the device and then nucleated byapplying microparticulate crystalline drug to the amorphous drug layer,followed by vapor annealing. These two may also be combined so thatmicrocrystalline drug is applied under and over the amorphous drug layerbefore vapor annealing.

The microcrystalline drug may be applied dry, using powder applicationequipment, for instance charged particle applicators or from suspension.The device may be dipped and withdrawn from an agitated suspension, orapplied using e.g. a spray or syringe to apply a dispersion of themicroparticulate drug, followed by drying. For a drug such as everolimusa suitable suspension vehicle for dispersing the microcrystalline drugis water. Suitable methods for preparing the microparticulatecrystalline drug include crystallizing the drug from solution or slurryand then grinding the drug crystals to the desired size range.

In some embodiments the microparticulate nucleating agent is provided onthe substrate, before application of the drug coating at a density offrom about 10 particle/mm² to about 5000 particles/mm², or from about100 particles/mm² to about 2000 particles/mm². The size of themicroparticulate drug nucleating agent may vary. In some embodiments theparticulate nucleating agent has its major dimension in the size rangeof from about 10 nm to about 20 μm, or from about 100 nm to about 10 μm.

Alternatively the amorphous coating may be generated first. Then amicrocrystalline layer applied, followed by solvent vapor annealing.

In at least some embodiments the microparticulate drug crystals in sucha coating have a mean particle size of less than about 10 μm as measuredby dynamic light scattering methods, for instance using photocorrelationspectroscopy, laser diffraction, low angle laser light scattering(LALLS), medium-angle laser light scattering (MALLS), light obscurationmethods (Coulter method, for example), rheology, or microscopy (light orelectron). The microparticles can be prepared in a wide range of sizes,such as from about 20 μm to about 10 nm, from about 10 μm to about 10nm, from about 2 μm to about 10 nm, from about 1 μm to about 10 nm, fromabout 400 nm to about 50 nm, from about 200 nm to about 50 nm or anyrange or combination of ranges therein. The crystalline particle size insome cases may be sized to a desired distribution using agitationmethods such as sonication during slurry aging. Alternatively a desiredparticle size may be obtained by mechanical grinding techniques such aspearl milling, a ball milling, hammer milling, fluid energy milling orwet grinding techniques or the like after the drug has been converted tocrystalline form.

In an exemplary method of preparing microparticulate everolimus, aslurry of the everolimus crystals in a non-solvent such as water orheptane is prepared in stainless steel ampule. Milling media (forinstance micro-beads of a hard durable material such as zircronia) isadded to the slurry. The ampule is placed on a high speed shaker andshaken at 4000 rpm for 20 min. The shaking process results in cascadingof the media in the ampule which acts to break the everolimus crystalinto small micro or nano-sized particles.

Alternatively a slurry of the everolimus crystals in a non-solvent suchas water or heptane may be prepared in a glass vial or bottle. Millingmedia (for instance micro-beads of a hard durable material such aszircronia) is added to the slurry. The vial or bottle may be placed on aroller mill for about 24 hr. The rolling process results in cascading ofthe media in the vessel which acts to break the everolimus crystals intosmall micro- or nano-sized particles.

Particle size is dictated by the diameter and composition of the millingmedia. Spherical media is available in various diameters and composition(densities). Reducing the diameter of the media usually results insmaller drug particles. Increasing the density of the media results ingreater milling energy and smaller drug particles. It is desirable tobreak the drug particles down to a size where a reasonably stablecoating dispersion can be obtained that can then be coated by variouscoating processes such as electrostatic spraying, powder spray, spincoaters. Exemplary coater systems include e.g., LabCoat®, or DirectWrite® (from Optimec) coating systems).

It is surprising that microcrystalline drug can be used as a nucleatingagent under the amorphous drug coating applied from solution. Generallyit was expected that the microcrystalline drug would dissolve if a drugsolution was applied to it unless the microcrystalline layer was sothick that it formed a weak boundary. Either way it was considered thatthat nucleation with microcrystalline drug particles should not providea reliable crystalline coating for a medical device.

Amorphous Drug Layer

The amorphous drug layer is suitably applied from solution, althoughother techniques may also be used. Solution coating provides goodsurface coverage and coating quality. When microcrystalline drug hasbeen applied before the amorphous drug layer, the solution applicationtechnique should be carried out in a way that provides rapid drying, sothat at least some of the microcrystalline drug survives to nucleatecrystallization in the vapor annealing step. The solution concentration,temperature, application technique and the pressure in an tank or vesselwhere the solution is applied can be manipulated to provide a suitabledrying rate. In some embodiments the amorphous drug layer is applied byspraying, dipping, roll coating, or the like.

In some embodiments the amorphous drug layer is applied by spraying,using equipment that allows for variation in nozzle pressure, distancefrom substrate, and gas mixing ratios to provide a coating that largelydries on route to the substrate so that the applied coating isessentially dry on impact. In some cases the amorphous drug layer isapplied so that enough of the solvent remains on impact to provide asmooth coating of the amorphous drug.

Vapor Annealing

The vapor annealing step is performed using a solvent that is effectiveto induce crystallization for the drug employed. The use of themicrocrystalline drug as nucleating agent has the advantage that it doesnot introduce another component to the device coating that needs to beaccounted for in evaluating the safety and efficacy of the coateddevice.

Examples of solvents that may be used include alcohols such as methanol,ethanol (EtOH), isopropanol (IPA), n-butanol, isobutyl alcohol ort-butyl alcohol; acetonitrile (ACN); ethers such as tetrahydrofuran(THF) isopropyl ether (IPE), diethyl ether (DEE); ketone solvents suchas acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK);halogentated solvents such as dichloromethane (DCM), monofluorobenzene(MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), ethyltrifluroacetate (ETFA); aliphatic hydrocarbons such as hexane, heptane,or the like; aromatic hydrocarbons, such as toluene or xylenes; andester solvents such as ethyl acetate. Mixed solvents, for instanceheptane/ethyl acetate, acetone/water, IPA/water, or IPA/THF, THF/heptanecan also be used.

In some cases a non-volatile solute may be mixed with the vaporannealing solvent to limit vapor pressure of the solvent in thetreatment chamber. If the solvent vapor pressure (partial pressure) istoo low no crystallization occurs. If too high there is a potential forthe coating to become too fluid and the coating can migrate on thestent. Generating the solvent vapor from a solution of a non-volatilesolute in the solvent allows adjustment of the solvent vapor pressure tobe optimized for a particular coating.

Vapor annealing time for forming the crystalline drug on the balloon mayrange widely, for instance from about 5 minutes to about 24 hours, oreven longer. A typical time may be at least 30 minutes up to about 16hours. The solvent suitably is one that induces crystallization of thedrug without attacking the substrate material of the device. In someembodiments an alcohol solvent is employed, for instance a C₁-C₄alcohol.

After the vapor annealing step the balloon catheter may be dried in avacuum oven or by exposure to ambient conditions. In some embodiments avacuum drying step may also contribute to improvement of coatingdurability as compared to ambient drying conditions.

An exemplary method of preparing a vapor annealed coating of Everolimusis as follows. An Element® (Boston Scientific Corporation) stent isfirst abluminally coated with microparticulate everolimus and dried. Themicroparticulate coating may be at or below gravimetric detection limits(about 2 μg or less). In a second coating step a solution of Everolimusis then abluminally coated via either electrospray, Direct Write™, or byAnilox roll coat in a therapeutic amount. The Everolimus as coated inthe second step is amorphous. The stent is vapor annealed by exposingthe stent to isopropyl alcohol vapor overnight to generate thecrystalline morphology. The drug can be coated with or without anexcipient. Examples of appropriate excipients are fatty acid and fattyacid derivatives.

The importance of seeding to production of a useful coating isillustrated in FIGS. 8 a and 8 b, provided for comparison. In FIG. 8 aan amorphous everolimus coating is shown, without seeding. FIG. 8 bshows the same coating after treatment with IPA vapor. As can be seenthe drug has migrated off of major areas of the stent and concentratedat particular points where very large needle-like crystals gave grown.The crystals have poor adherence to the stent and their large size makesit easy to dislodge them.

Mixed Form Coatings

In addition to creating coatings of a specific drug crystalline form itis desirable to prepare a device coating that possesses a blend ofamorphous and crystalline forms within the same coating. The fasterdissolving amorphous drug will provide for initial burst release to thevessel and crystalline phase(s) will provide for slower dissolution intothe vessel for sustained tissue levels. This can be accomplished forexample by first applying a minor layer of microcrystalline drug,suitably from suspension in a non-solvent. Next, generate an amorphouscoating. Finally subjecting the amorphous coating to solvent vaporannealing (e.g. isopropanol vapor) for time intervals less than requiredto achieve 100% crystallinity will lead to a coating with a mix ofamorphous and crystalline phases. A specific rate of drug release fromthe coating may be tailored by varying the ratio of these drugpolymorphs with different solubility and dissolution rates in a singlecoating.

In some embodiments the fraction of amorphous drug in the coating isfrom 0-25%, for instance about 1%, about 2%, about 3%, about 5%, about6%, about 8%, about 10%, about 12%, about 15%, about 18%, about 20%,about 22%, or about 25%, based on total drug weight. In some embodimentsthe fraction of crystalline drug is from 1% to 100%, for instance 1-99%,5-95%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 88%, about 89%, about 90%,about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about97%, about 98%, about 99% or about 100%, based on total drug weight.

Coat Weight

In some embodiments a drug coating of drug on a device such as a sent ordrug delivery balloon contains from 10 to 1000 μg of drug, for instance10-200 μg, 200-800 μg, 300-600 μg, or 400-500 μg of everolimus. In someembodiments the amount of amorphous drug on the device is from 0-80 μg,less than 60 μg, or less than 30 μg, with the remaining being acrystalline form.

In some embodiments the amount of amorphous drug on the device is from0-80 μg, less than 60 μg, or less than 30 μg, with the remaining beingone or both crystalline forms. In some embodiments the amount ofcrystalline drug on the device is from 10 to 1000 μg, 10-200 μg, 100-800μg, 200-600 μg, 300-500 or 350-450 μg.

In some embodiments the fraction of amorphous drug in the coating isfrom 0-25%, for instance about 1%, about 2%, about 3%, about 5%, about6%, about 8%, about 10%, about 12%, about 15%, about 18%, about 20%,about 22%, or about 25%, based on total drug weight. In some embodimentsthe fraction of crystalline drug is from 1% to 100%, for instance 1-99%,5-95%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 88%, about 89%, about 90%,about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about97%, about 98%, or about 99%, based on total drug weight.

The invention is illustrated by the following non-limiting examples.

Example 1 Generation of Crystalline Everolimus Via Seeding and VaporAnnealing

a. Preparation of Microcrystalline Everolimus

Amorphous everolimus is dissolved in isopropyl alcohol at 40 wt % withgentle warming at ˜40 C. The solution is allowed to sit at RT overnightresulting in crystallization of the everolimus. The large crystals aredried under vacuum at RT. 0.1 g of crystalline everolimus, 0.16 g waterand 1.85 g of 100 um Zirconia beads are added to a SS ampule. The ampuleis sealed and placed on a high speed amalgamator shaker for 20 min.Water (2 mL) is added to the resulting paste and the mixture is swirledto disperse the milled everolimus particles.

The water/everolimus dispersion is decanted off from the Zr beads andfiltered through a 30 um nylon mesh filter. The Zr bead slurry is washedan additional 3 times using about 2 mL water each time and each time thewater/everolimus dispersion is filtered through 30 μm nylon mesh filter.The combined filtered dispersion is centrifuged at 4000 rpm for 10 min.The supernatant is decanted off until there is about 1-2 mL of liquidremaining in the centrifuge tube along with the everolimus particles.The concentrated particle dispersion is transferred to a vial. Thecentrifuge tube is then rinsed 2-3 times with 0.1-0.2 mL DI water (eachrinse) and added to the vial (to transfer residual dispersion clingingto the walls of the centrifuge tube). The resulting everolimusdispersion in water is about 3 wt % solids. Yield is about 70%. Averageparticle size is about 1 μm.

b. Seeding, Coating and Vapor Annealing of Everolimus Coated Stents

The aqueous microcrystalline everolimus dispersion resulting fromExample 1a is sprayed onto 16 mm stents using an electrospray process.Flow rate is 0.5 mL/hr. Spray time is 20-30 sec. A very small amount ofthe everolimus particles are coated on the stent. The coat weight wastoo little to quantify gravimetrically (a rough estimate is 1-3 μg. FIG.3 shows a representative SEM of the seeded stent showing traces ofmicrocrystalline everolimus.

The seeded stent is then coated via electrospray with everolimus (3%everolimus in 1:1 THF:IPA. Flow rate is 2-3 mL/hr). The coat wt of theamorphous drug layer is 100-200 μg.

FIG. 4 shows a representative SEM of a stent coated with amorphouseverolimus using a nominal spray process which provides a smoothcoating.

FIGS. 5 a and 5 b show a representative SEM of a stent coated withamorphous everolimus using a dry spray process, at two differentmagnifications. The dry spray is produced by the same apparatus byincreasing the distance, reducing the flow rate but increasing the spraytime, to give an equivalent weight coating. The dry spray processresults in a more porous (matte-like) coating but remains amorphous.

The vapor annealing process is conducted as follows: About 2 mL of 70/30(wt/wt) of IPA/glycerol is added to the bottom of the 8 oz jar. Thestents are suspended above the liquid. The jar is sealed at RT for ˜24hr. The glycerol is a non-volatile solute used to control the vaporpressure of the IPA in the jar. It has been found that the resultingcrystalline morphology is impacted by the IPA vapor concentration in thejar. A 75/25 ratio of IPA/glycerol was found to give optimal crystalmorphology.

FIG. 6 shows a representative SEM of a vapor annealed seeded stent(using the nominal everolimus coating).

FIGS. 7 a and 7 b show representative SEM of a vapor annealed seed stent(using the dry everolimus coating process), at two differentmagnifications. A very small, uniform crystalline structure is formedduring vapor annealing.

Differential scanning calorimetry (DSC) of vapor annealed everolimusshows a crystalline melting endotherm at 154 C. There is no visibleglass transition (Tg) at about 80 C (the Tg of amorphous everolimus isabout 80 C). Thus DSC shows that vapor annealed everolimus iscrystalline.

Comparative Example Vapor Anneal without Seeding

As a comparative example of omitting the microparticulate crystallinedrug, method a solution of Everolimus is abluminally coated onto anElement® (Boston Scientific Corporation) stent via electrospray similarto Example 1. The everolimus as coated is amorphous (FIG. 8 a). Thestent is vapor annealed by exposing the stent to isopropyl alcohol vaporovernight (FIG. 8 b) to generate the crystalline morphology. As can beseen, the drug has migrated. The crystals are very long needles poorlyadhered to the stent.

Example 2 Porcine Animal Study of Everolimus Coated Stents

Stents coated with either crystalline or amorphous everolimus (130 μg on12 mm stents) were implanted in the coronary arteries and internalthoracic arteries of common swine. The stented vessels were explantedafter 3 hrs, 24 hrs, 7, 14 and 28 days. N=3 stents per timepoint wereused. After sacrifice the stents were removed from the arteries and theamount of drug in the arteries was determined by LC/MS. The amount ofdrug remaining on the stent was determined by HPLC. Table 1 shows theamount of drug remaining in the tissue after 28 days and the amount ofdrug remaining on the stents. There is essentially no drug in the tissueat 28 days for stents coated with amorphous everolimus compared to 6ng/mg for crystalline everolimus. There was no drug remaining on thestents after 28 days for the amorphous drug compared to 25% drugremaining on the stent with crystalline everolimus. This example showsthe significant benefit of using the slower dissolving/lower solubilitycrystalline form of the drug in maintaining significant drug tissuelevels.

TABLE 1 Tissue content % drug left on Stent coating at 28 days stent at28 days Amorphous Everolimus 0.04 ng/mg 0 Crystalline Everolimus 6.1ng/mg 25.8

Example 3 Crystalline Everolimus Coated Balloon Via Seeded VaporAnnealing

A 3 mm×16 mm balloon was syringe coated with 2 μL of a 1.4% solidseverolimus microdispersion to provide the seeding layer. The coating wasallowed to dry at RT. The balloon was then coated with 11 μL of a 3.8%soln. of everolimus in 75/25 (wt/wt) acetone/water to give a coat wt ofabout 3 ug/mm2 The balloon was vapor annealed with IPA vapor overnightto crystallize the everolimus. FIG. 10 shows a SEM image of the balloonshowing the presence of crystalline everolimus.

Example 4 Coating of Balloon with Microcrystalline Everolimus

A 3 mm×16 mm balloon was syringe coated with 15 μL of ˜3% everolimusmicrodispersion in water. The coating was dried at RT. The resultingdrug content was 3 μg/mm². FIG. 9 shows SEM images of the coated balloonshowing the morphology of the microparticles of everolimus at 4magnifications.

Other coating processes can be utilized which would allow one toabluminally coat crystalline drug or both amorphous and crystallinedrug. For example, Direct Write® (Optimec) allows one to abluminallycoat discrete dots of drug. FIG. 11 shows an example of a coating ofdiscrete dots of a drug on a substrate. Using this coating process onecan first partially coat the stent with discrete dots of everolimus. Thestent can then be vapor annealed to generate crystalline drug dots. Thisis illustrated in FIG. 12, wherein a portion 12 of a stent 10 is shownhaving dots of crystalline drug 14 thereon.

The stent 20 illustrated in FIG. 13, is prepared in a manner similar tothe stent 10 of FIG. 12, but after forming crystalline drug dots 14 samestent can again be coated with discrete dots 18 of amorphous drug. Thestent is not subsequently vapor annealed—leaving the second coatingamorphous. In this way one can modulate release by having amorphouseverolimus to give predominately burst release and crystallineeverolimus to provide predominately sustained release. The balance ofburst to sustained release can by adjusted independently through controlof the proportional coat weights of the amorphous and crystalline dots.

In still another embodiment, not shown, the microparticulate crystallinedrug and the amorphous drug are coated onto a stent with troughs ordepressions on the surface, either applying the drug directly into thetroughs or depressions only, or onto the stent followed by removal, e.g.by wiping, from the portions of the stent outside the troughs. Vaporannealing produces a drug coating in accordance with the invention thatis confined to the troughs or depressions. This provides some additionalprotection for the crystalline drug coating during delivery while stillallowing the benefit of a polymer-free drug that provides extendedrelease.

All published documents, including all US patent documents, mentionedanywhere in this application are hereby expressly incorporated herein byreference in their entirety. Any copending patent applications,mentioned anywhere in this application are also hereby expresslyincorporated herein by reference in their entirety.

The above examples and disclosure are intended to be illustrative andnot exhaustive. These examples and description will suggest manyvariations and alternatives to one of ordinary skill in this art. Allthese alternatives and variations are intended to be included within thescope of the claims, where the term “comprising” means “including, butnot limited to”. Those familiar with the art may recognize otherequivalents to the specific embodiments described herein whichequivalents are also intended to be encompassed by the claims. Further,the particular features presented in the dependent claims can becombined with each other in other manners within the scope of theinvention such that the invention should be recognized as alsospecifically directed to other embodiments having any other possiblecombination of the features of the dependent claims. For instance, forpurposes of claim publication, any dependent claim which follows shouldbe taken as alternatively written in a multiple dependent form from allclaims which possess all antecedents referenced in such dependent claimif such multiple dependent format is an accepted format within thejurisdiction. In jurisdictions where multiple dependent claim formatsare restricted, the following dependent claims should each be also takenas alternatively written in each singly dependent claim format whichcreates a dependency from an antecedent-possessing claim other than thespecific claim listed in such dependent claim.

1. A medical device having a polymer-free outer surface layer on atleast a portion thereof, said layer comprising a crystalline drugselected from the group consisting of everolimus, tacrolimus, sirolimus,zotarolimus, biolimus, and rapamycin.
 2. A medical device as in claim 1wherein the drug is everolimus.
 3. A medical device as in claim 2wherein the crystalline form everolimus comprises at least 85% by weightof the drug.
 4. A medical device as in claim 10 wherein the crystallineform everolimus comprises at least 90% by weight of the drug.
 5. Amedical device as in claim 2 wherein the polymer-free coating comprisesa mixture of crystalline and amorphous everolimus, the mixturecomprising from 15% to 90% by weight of said crystalline everolimus. 6.A medical device as in claim 1 wherein the crystalline layer isformed-in-place with a crystalline morphology having a generallyrectilinear form characterized by a major dimension of length and minordimensions of width and thickness.
 7. A medical device as in claim 6wherein said crystalline morphology is formed by individual crystalshaving with an average length of less than 50 μm, an average width ofless than 10 μm and an average thickness of less than 1.5 μm.
 8. Amedical device as in claim 1 wherein said outer surface layer furthercomprises a non-polymeric excipient.
 9. A medical device as in claim 8wherein said non-polymeric excipient is a wax, fat, oil or a citrateester.
 10. A medical device as in claim 1 wherein said outer surfacelayer is free of any excipient.
 11. A medical device as in claim 1wherein the medical device is a stent, a catheter balloon, guide wire,heart valve, catheter, vena cava filter, vascular graft or a stentgraft.
 12. A medical device as in as in claim 1 wherein the device is ametal stent, the outer layer is free of any excipient, and the coatingis provided in grooves or depressions on the outer surface of the stent.